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BACKGROUND: In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers. METHODS: We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res). RESULTS: In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions. CONCLUSIONS: Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.
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The relationship between allergic diseases and cancer is a very controversial topic, widely discussed in the last decades. Many studies have demonstrated inverse association between allergy and cancer, but others have reached neutral conclusions or have indicated a positive role of allergy in the development of cancer. However, either inhibiting or favoring, many cells and molecules relevant in the allergic process play a role in tumorigenesis. On the one hand, activated immune cells, like classically activated macrophages "M1", activated dendritic cells, IL-33 and amphiregulin stimulated Innate Lymphoid Cells (ILC2), Th1, IFN-γ producing T CD8+ and B lymphocytes have inhibitory effects on tumorigenesis and tumor progression. On the other hand, tolerogenic immune cells, like alternatively activated macrophages "M2" (M2a, M2b and M2c), tolerogenic dendritic cells, ILC3, T regulatory and B regulatory lymphocytes, while inhibiting allergic sensitization and response, appear to favour carcinogenesis. Furthermore, M2 subtypes macrophages (M2a, M2b), IL-25 stimulated ILC2 and Th2 lymphocytes have a role both in inducing allergic reactions and in favouring cancer progression. In addition, mast cells, pivotal cells in allergy, have a different effect of tumorigenesis based on their location - they can promote cancer progression or inhibit it. Finally, eosinophils have shown a prevalent tumoricidal function mediated by α-defensins, TNF-α, granzymes A and IL-18. Better understanding the role of various cells on carcinogenesis can help in developing new strategies (diagnostic, therapeutic and of follow up) against tumor.
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Hipersensibilidad/complicaciones , Inmunidad Innata , Neoplasias/complicaciones , Linfocitos B/citología , Carcinogénesis , Transformación Celular Neoplásica , Eosinófilos/citología , Humanos , Macrófagos/citología , Linfocitos T/citologíaRESUMEN
[This corrects the article DOI: 10.1155/2019/5879616.].
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The recent introduction of the "precision medicine" concept in oncology pushed cancer research to focus on dynamic measurable biomarkers able to predict responses to novel anticancer therapies in order to improve clinical outcomes. Recently, the involvement of extracellular vesicles (EVs) in cancer pathophysiology has been described, and given their release from all cell types under specific stimuli, EVs have also been proposed as potential biomarkers in cancer. Among the techniques used to study EVs, flow cytometry has a high clinical potential. Here, we have applied a recently developed and simplified flow cytometry method for circulating EV enumeration, subtyping, and isolation from a large cohort of metastatic and locally advanced nonhaematological cancer patients (N = 106); samples from gender- and age-matched healthy volunteers were also analysed. A large spectrum of cancer-related markers was used to analyse differences in terms of peripheral blood circulating EV phenotypes between patients and healthy volunteers, as well as their correlation to clinical outcomes. Finally, EVs from patients and controls were isolated by fluorescence-activated cell sorting, and their protein cargoes were analysed by proteomics. Results demonstrated that EV counts were significantly higher in cancer patients than in healthy volunteers, as previously reported. More interestingly, results also demonstrated that cancer patients presented higher concentrations of circulating CD31+ endothelial-derived and tumour cancer stem cell-derived CD133 + CD326- EVs, when compared to healthy volunteers. Furthermore, higher levels of CD133 + CD326- EVs showed a significant correlation with a poor overall survival. Additionally, proteomics analysis of EV cargoes demonstrated disparities in terms of protein content and function between circulating EVs in cancer patients and healthy controls. Overall, our data strongly suggest that blood circulating cancer stem cell-derived EVs may have a role as a diagnostic and prognostic biomarker in cancer.
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Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.
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Neoplasias de la Mama/terapia , Predisposición Genética a la Enfermedad , Inmunoterapia , Receptor ErbB-2/genética , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Femenino , HumanosRESUMEN
All fields of industry are applying nanotechnologies for the development of advanced materials, there¬fore at present the number of workers exposed to nanosized materials are significantly increasing. Unfortunately, protective equipment for nanoparticles (NPs) is of uncertain efficacy so the risk of noxious effects, in particular allergic sensitization, on workers gives many concerns. At the same time, studies of allergic physiopathology demonstrated that the lack of prevention and treatment could result in invalidating dis¬eases that, in case of professional etiology, might imply removal from the job and compensation. Therefore, a deeper knowledge of the role of NPs in inducing allergic diseases is mandatory to implement the risk assessment and preventive measures for nanosafety in the workplace. The possibility that NPs favor, ex¬acerbate or directly induce allergy is being suggested by recent experimental investigations in cellular and animal models. Unfortunately, studies are heterogeneous and few data have received experimental confir¬mation, lacking reproducibility. What comes to attention is the uncertainty about the real plausibility of the observed experimental effects, as there are only a few reported cases of allergy onset or exacerbation for workers exposed to NPs. However, the potential for NPs to induce, favor or exacerbate allergies seems possible even though not completely demonstrated. This should be a greater incentive to carry out appro¬priate epidemiological studies that are lacking and really needed.
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Hipersensibilidad/etiología , Nanopartículas/efectos adversos , Enfermedades Profesionales/etiología , Exposición Profesional/efectos adversos , Animales , Humanos , Reproducibilidad de los Resultados , Medición de RiesgoRESUMEN
Nectins are Ca(2+)-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan-Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4(High)). At Kaplan-Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4(High) was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4(Low/Negative) is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.
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The ErbB receptors, such as ErbB-1 and ErbB-2, have been intensely pursued as targets for cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance, which is often associated with reactivation of the ErbB-3-PI3K-Akt signaling. This may be overcome by an ErbB-3 ligand that abrogates receptor-mediated signaling. Toward this end, we have generated a mouse monoclonal antibody, MP-RM-1, against the extracellular domain (ECD) of ErbB-3 receptor. Assessment of human tumor cell lines, as well as early passage tumor cells revealed that MP-RM-1 effectively inhibited both NRG-1ß-dependent and -independent ErbB-3 activation. The antagonizing effect of MP-RM-1 was of non-competitive type, as binding of [(125)I]-labeled NRG-1ß to ErbB-3 was not influenced by the antibody. MP-RM-1 treatment led, in most instances, to decreased ErbB-3 expression. In addition, MP-RM-1 was able to inhibit the colony formation ability of tumor cells and tumor growth in two human tumor xenograft nude mouse models. Treatment with the antibody was associated with a decreased ErbB-3 and Akt phosphorylation and ErbB-3 expression in the excised tumor tissue. Collectively, these results indicate that MP-RM-1 has the potential to interfere with signaling by ErbB-3 and reinforce the notion that ErbB-3 could be a key target in cancer-drug design.
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Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-akt/fisiología , Receptor ErbB-3/antagonistas & inhibidores , Transducción de Señal/fisiología , Animales , Línea Celular Tumoral , Humanos , Ligandos , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Fosforilación , Multimerización de Proteína , Receptor ErbB-3/fisiología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An unknown primary tumor (UPT) is defined by the presence of a metastatic cancer without a known primary site of origin despite a standardized diagnostic workup. Clinically, UPTs show rapid progression and early dissemination, with signs and symptoms related to the metastatic site. The molecular bases of their biology remain largely unknown, with no evidence as to whether they represent a distinct biological entity. Immunohistochemistry remain the best diagnostic tool in term of cost-effectiveness, but the time-consuming "algorithmic process" it relies on has led to the application of new molecular techniques for the identification of the primary site of UPTs. For example, several microarray or miRNA classifications of UPTs have been used, with an accuracy in the prediction of the primary site as high as 90%. It should be noted that validating a prediction of tissue origin is challenging in these patients, since most of them will never have a primary site identified. Moreover, prospective studies to determine whether selection of treatment options based on such profiling methods actually improves patient outcome are still missing. In the last few years functional imaging (i.e. FDG-PET/CT) has gained a main role in the detection of the site of origin of UPTs and is currently recommended by the European Association of Nuclear Medicine. However, despite recent refinements in the diagnostic workup, the site of origin of UPT often remains elusive. As a consequence, treatment of patients with UPT is still empirical and inadequate.
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Neoplasias Primarias Desconocidas/genética , Animales , Perfilación de la Expresión Génica , Humanos , MicroARNs/análisis , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/patología , Neoplasias Primarias Desconocidas/terapiaRESUMEN
Irinotecan hydrochloride (CPT-11) can display severe toxicities in individual cancer patients. CPT-11 is bio-activated through CES, detoxified through UGT1A1 and inhibits TOP1. CPT-11 toxicity and UGT1A1, CES2 and TOP1 mRNAs and UGT1A1 protein were determined in male and female C57BL/6, B6D2F1 and B6CBAF1, as potential models for tailoring CPT-11 delivery. CPT-11 was administered intravenously (40-90 mg/kg/day for 4 days at 7h after light onset). The relations between dose and lethal toxicity or body weight loss were steep and similar in C57BL/6 (lethality, p=0.001; weight loss, p=0.002) and B6D2F1 (p=0.01; p=0.03, respectively), but weak in B6CBAF1. Females displayed less toxicity than males (p<0.001). Mean mRNA expression of UGT1A1 was highest in B6CBAF1 (p=0.039) and in females (p<0.001). Both CES2 and TOP1 varied according to strain and gender (p<0.001). The three gene expression data explained the most severe toxicity of CPT-11 in male B6D2F1, but displayed inconsistent relations with toxicity in the other groups. Mean UGT1A1 protein expression was highest in males as compared to females, and so by approximately 8-fold in C57BL/6 as compared to B6D2F1 (p<0.0001). Genetic background and gender significantly altered the molecular prediction of irinotecan toxicity by UGT1A1, CES2 and TOP1 mRNA expressions.
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Camptotecina/análogos & derivados , Hidrolasas de Éster Carboxílico/biosíntesis , ADN-Topoisomerasas de Tipo I/biosíntesis , Glucuronosiltransferasa/biosíntesis , Animales , Camptotecina/toxicidad , Carboxilesterasa , Relación Dosis-Respuesta a Droga , Femenino , Expresión Génica/efectos de los fármacos , Irinotecán , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Endogámicos , Factores Sexuales , Especificidad de la EspecieRESUMEN
BACKGROUND: This phase II study was conducted to evaluate tumor response rate and safety profile of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine given preoperatively to patients with stage II or IIIA breast cancer. PATIENTS AND METHODS: Patients underwent four cycles of dose-dense cyclophosphamide 600 mg/m(2) and epirubicin 90 mg/m(2) every 2 weeks followed by two cycles of docetaxel 36 mg/m(2) on days 1, 8, and 15 plus capecitabine 1250 mg/m(2) on days 5-18 every 4 weeks, with prophylactic pegfilgrastim. The primary objective of the study was to determine the incidence of pathologic complete response defined as the absence of invasive or in situ cancer in the breast and the axillary nodes at definitive surgery. RESULTS: Forty-four patients were enrolled in the study and 41 (93%) were assessable for response to chemotherapy. An objective clinical response was observed in 38 (93%) patients. Seven patients (17.1%) exhibited a pathologic complete response. Breast-conserving surgery was carried out in 36 (88%) patients. Grade 3/4 neutropenia occurred in 4.3% of 252 administered chemotherapy cycles. No febrile neutropenia, cardiac toxicity, thrombocytopenia or other serious adverse event was registered. CONCLUSION: The sequential combination of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine is an effective and well-tolerated neo-adjuvant chemotherapy for stage II, IIIA breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Docetaxel , Esquema de Medicación , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Polietilenglicoles , Posmenopausia , Premenopausia , Cuidados Preoperatorios , Proteínas Recombinantes , Taxoides/administración & dosificaciónRESUMEN
A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adolescente , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Irinotecán , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Factores de TiempoRESUMEN
To clarify the biological role of the 90K/Mac-2BP glycoprotein, we evaluated the ability of two MAbs SP-2 and 1A4.22, to reveal this glycoprotein in both serum and tissue from hepatocellular carcinoma (HCC) patients. Tissue expression of 90K was detected by the immunohistochemical method in 20 HCC patients, while the 90K serum level was assessed by the ELISA assay in 13 HCC patients. MAb SP-2 was reactive only in serum, with a mean value of 12.8+/- 6.7 microg/ml . On the contrary, MAb 1A4.22 revealed immunoreactivity both in 92% of sera and in 60% of neoplastic samples. Positive staining was seen only in the epithelial cells and was cytoplasmic and granular in all instances. The mean 90K serum level assayed with MAb 1A4.22 was 29.4 +/- 13.7 microg/ml. Patients with a 90K serum level
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Anticuerpos Monoclonales , Especificidad de Anticuerpos , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/inmunología , Carcinoma Hepatocelular/inmunología , Células Epiteliales/inmunología , Glicoproteínas de Membrana/análisis , Glicoproteínas de Membrana/inmunología , Anciano , Anticuerpos Monoclonales/química , Antígenos de Neoplasias/sangre , Carcinoma Hepatocelular/patología , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/patología , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Glicoproteínas de Membrana/sangre , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
A dose-finding study was undertaken to determine the maximum-tolerated dose, and the recommended dose of docetaxel in combination with 12-h timed (22:00-10:00) flat infusion of 5-fluorouracil (5-FU) in metastatic breast cancer patients. This schedule seems to reduce the occurrence of stomatitis of the docetaxel and infusional 5-FU regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Docetaxel , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Taxoides/administración & dosificaciónRESUMEN
OBJECTIVES: To evaluate the level of 90K as a predictor of AIDS; to describe 90K levels over time after HIV serconversion; and to evaluate the 90K level as a marker of the maturity of infection. DESIGN: Prospective incident cohort of HIV-infected individuals with documented dates of seroconversion. METHODS: Cox models were applied to estimate the crude and adjusted relative hazards (RH) of AIDS by level of 90K. Regression models were applied to describe the temporal trend and the correlates of the level of 90K over time after HIV-seroconversion. Logistic models were applied to evaluate the probability of a sample of 90K having been taken within a certain time period after HIV-seroconversion. RESULTS: The study population consisted of 150 participants of the Italian Seroconversion Study. A total of 429 measurements of 90K were taken. Both early and later measurements of 90K were highly predictive of AIDS, also when adjusting for CD4 lymphocyte count and HIV load. The 90K level (U/ml) increased by 10% annually (95% CI: 7%-13%); the increase over time was linear. IDUs had higher 90K levels than heterosexuals and homosexuals over the course of HIV disease. High 90K levels were highly predictive of distant seroconversions (age-adjusted probability, 74%), whereas were poorly predictive of recent seroconversions (age-adjusted probability, 5%); the results were similar for the predictability of CD4 lymphocyte count. CONCLUSIONS: The level of 90K is a useful prognostic tool for clinical purposes. As a marker of the maturity of infection, 90K is similar to the CD4 lymphocyte count, with the advantage of being able to use serum instead of fresh whole blood. It has a good capacity to identify distant infections.
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Glicoproteínas/química , Infecciones por VIH/epidemiología , Infecciones por VIH/metabolismo , Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Adolescente , Adulto , Antígenos de Neoplasias , Terapia Antirretroviral Altamente Activa , Biomarcadores de Tumor , Linfocitos T CD4-Positivos/metabolismo , Proteínas Portadoras , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Glicoproteínas/metabolismo , Seropositividad para VIH , Humanos , Italia , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Análisis de Regresión , Factores de Riesgo , Factores de TiempoRESUMEN
The glycoprotein 90K was originally described as a tumor-secreted antigen and subsequently found to have immunostimulatory activity as well as other possible functions. This protein interacts with an endogenous lectin, galectin-3, and may play a role in tumor metastasis through this interaction. Because 90K is heavily glycosylated, it may also interact with other members of the galectin family, which would contribute to the multifunctionality of 90K. To test this possibility, we studied the recognition of 90K by galectin-1, which, like galectin-3, has been associated with neoplastic transformation. In a solid-phase binding assay, human recombinant galectin-1 bound immobilized human recombinant 90K in a fashion that was inhibitable by lactose. Galectins 1 and 3 appeared to bind to separate sites on 90K because they did not affect the binding of each other. The dissociation constant of galectin-1 to 90K was on the order of 10(-7) M. Galectin-1 also induced aggregation of a human melanoma cell line, A375, in a carbohydrate-dependent manner, and this appeared to be mediated, at least in part, by 90K expressed on A375 cells, since it was inhibitable by a specific anti-90K monoclonal antibody. We conclude that 90K interacts with both galectin-1 and galectin-3 and both interactions contribute to the formation of multicell aggregates. Because both of these galectins as well as 90K are often over-expressed in neoplasm, these interactions may occur in the setting of various carcinomas and contribute to their progression and metastasis.
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Glicoproteínas/metabolismo , Hemaglutininas/metabolismo , Células 3T3 , Animales , Antígenos de Diferenciación/metabolismo , Agregación Celular , Galectina 1 , Galectina 3 , Humanos , Melanoma/patología , Ratones , Peso Molecular , Células Tumorales CultivadasRESUMEN
A cell-adhesive protein of the human serum, 90K binds galactin-3, beta1-integrins, collagens, and fibronectin, and it is of importance in cell-cell and cell-extracellular matrix adhesion. Serum 90K levels in 137 patients with lymphoma were measured by enzyme-linked immunosorbent assay. Compared with healthy controls, pretreatment serum 90K levels in patients with lymphoma were elevated (P <.001). Of 97 patients who showed objective response to treatment, 20 (21%) had pretreatment 90K levels above the normal cutoff compared with 17 (53%) of 32 patients who did not respond (P =.002). When used as a plastic-immobilized substrate, 90K caused a significant reduction in chemotherapy-induced apoptosis of Jurkat T lymphoma cells. This finding could explain the lack of response in lymphoma patients with high 90K serum levels.
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Antineoplásicos/uso terapéutico , Proteínas Portadoras/sangre , Adhesión Celular/fisiología , Resistencia a Múltiples Medicamentos , Glicoproteínas/sangre , Linfoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/sangre , Ciclofosfamida/toxicidad , Doxorrubicina/toxicidad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Células Jurkat , Linfoma/sangre , Linfoma/clasificación , Linfoma de Células B/sangre , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células T/sangre , Linfoma de Células T/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
BACKGROUND: The chronomodulated infusion of 5-FU, FA and oxaliplatin allows a significant increase in dose intensity and antitumor efficacy in patients with metastatic colorectal cancer. Here we investigated if substitution of oxaliplatin with cisplatin produced a similar antitumor activity in previously untreated patients with advanced colorectal cancer. METHODS: We enrolled 21 consecutively evaluated ambulatory patients with metastatic colorectal cancer. Each treatment cycle consisted of a 5-day course of continuous chronomodulated venous infusion of drugs. Daily doses were 600 mg/m2 5-FU, 150 mg/m2 FA (L-form), and 12 mg/m2 cisplatin. The cycles were repeated every 21 days. RESULTS: All patients completed at least 3 cycles. Overall a total number of 105 cycles were administered. One partial response (lasting 3 months) and 13 stable disease (lasting from 3 to 12 months) were observed. The remaining 7 patients had progression of the disease. Hematologic and gastrointestinal toxicity was always < or = G2 in all cycles. CONCLUSIONS: The results of this study discourage the substitution of cisplatin for the more active compound, oxaliplatin, in a chronomodulated schedule of infusion with 5-FU and FA in patients with metastatic colorectal cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ritmo Circadiano , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Adulto , Anciano , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Neoplasias del Colon/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias del Recto/patologíaRESUMEN
Galectins are a family of proteins involved in several cell processes, including their survival and death. Galectin-3 has in particular been described as an anti-apoptotic molecule entangled with a number of subcellular activities including anoikis resistance. In this work we partially address the mechanisms underlying this activity pointing at two key factors in injury progression: the alteration of mitochondrial membrane potential and the formation of reactive oxygen species. Overexpression of galectin-3 appears in fact to exert a protective effect towards both these events. On the basis of these data, we propose a reappraisal of the role of galectin-3 as a regulator of mitochondrial homeostasis.
Asunto(s)
Antígenos de Diferenciación/metabolismo , Glicoproteínas de Membrana/metabolismo , Mitocondrias/fisiología , Muerte Celular/fisiología , Femenino , Galectina 3 , Homeostasis , Humanos , Membranas Intracelulares/fisiología , Potenciales de la Membrana , Microscopía Electrónica de Rastreo , Mitocondrias/ultraestructura , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/farmacología , Vitamina K/farmacologíaRESUMEN
Galectin-3, a member of the beta-galactoside-binding animal lectins, has been implicated in tumor invasion and metastasis. Using an immunoligand assay, we assessed the circulating levels of galectin-3 in sera from cancer patients as well as from healthy controls. Low serum levels of galectin-3 were detected in healthy individuals (median, 62 ng/ml; range, 20-313 ng/ml; 95th percentile, 184.3 ng/ml). Compared with healthy individuals, galectin-3 serum levels in patients with breast, gastrointestinal, lung, or ovarian cancer, melanoma, and non-Hodgkin's lymphoma were significantly elevated (P = 0.014). Moreover, galectin-3 concentrations in sera from patients with metastatic disease were higher than in sera from patients with localized tumors. Maximum serum concentrations of galectin-3 (median, 320 ng/ml; range, 20-950 ng/ml) were found in patients with metastatic gastrointestinal carcinoma. These results suggest that circulating galectin-3 may play a role in tumor progression. The possibility of using this assay in early-stage cancer to predict metastasis should be studied.